Abstract

2365

Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of gastric cancer. The major targets of NSAIDs are COX-1 and COX-2. Of these two iso-enzymes, expression of COX-2 is elevated in human gastric cancer tissues, suggesting its roles in gastric tumorigenesis. On the other hand, it has been reported that microsomal prostaglandin E synthase (mPGES)-1 is induced in several human cancer tissues. Recent studies showed that prostaglandin E2 (PGE2) appears to be most responsible for cancer development, and COX-2 and mPGES-1 are functionally coupled for PGE2 biosynthesis. However, the role of PGE2 in tumor tissues produced by the COX-2/mPGES pathway has not yet been elucidated. To investigate the role of PGE2 in the gastric tumorigenesis, we constructed transgenic mice (K19-C2mE mice) simultaneously expressing COX-2 and mPGES in the epithelial cells of gastric mucosa. The K19-C2mE mice developed mucous cell metaplasia, hyperplasia and hyperplastic tumors in the glandular stomach with inflammatory cell infiltrations, reminiscent of the mice infected with Helicobacter pylori. Histologically, the K19-C2mE mice showed elongated pits and mucous cell metaplasia in the gastric body. Increased mucous cells contained Alcian blue-positive mucins, suggesting impaired differentiation of the mucous epithelium. Moreover, the BrdU incorporation rate in the K19-C2mE mice was twice as high as those in the wild-type mice. Subsequently, all K19-C2mE mice developed hyperplastic tumors in the proximal glandular stomach with mononuclear cell infiltration in the submucosa. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed the inflammatory responses and gastric hyperplasia. Interestingly, the antibiotic treatment did not affect the enhanced accumulation of mucosal macrophages in the transgenic mice. On the other hand, inhibition of proinflammatory cytokine production by treatment with pentoxyfilline suppressed the gastric hyperplasia. These results indicate that increased PGE2 levels in the gastric mucosa are responsible for the enhanced mucosal macrophage infiltration, and that their activation by the normal gastric flora causes gastric metaplasia and hyperplastic tumor development through proinflammatory cytokine productions.